Open AccessSynthesis and biological evaluation of antagonists of growth hormone-releasing hormone with high and protracted in vivo activities
Author(s) -
József Varga,
Andrew V. Schally,
Valér Csernus,
Márta Zarándi,
Gábor Halmos,
Kate Groot,
Zoltán Rékási
Publication year - 1999
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.96.2.692
Subject(s) - in vivo , hormone , growth hormone , human growth hormone , pharmacology , chemistry , computational biology , biology , medicine , endocrinology , biochemistry , microbiology and biotechnology
Some antagonists of human growth hormone-releasing hormone (hGH-RH) synthesized previously were shown to inhibitin vivo proliferation of various human cancers in nude mice. However, the activity of these analogs requires an increase to assure clinical efficacy. In an attempt to prepare hGH-RH antagonists with a high and protracted activity, we synthesized and biologically tested 22 antagonistic analogs of hGH-RH(1–29)NH2 . The ability of the antagonists to inhibit hGH-RH-induced GH release was evaluatedin vitro in a superfused rat pituitary system, as well asin vivo after i.v. injection into rats. The binding affinity of the peptides to GH-RH receptors also was determined. All antagonistic analogs had the common core sequence [PhAc-Tyr1 ,d -Arg2 , Phe(4-Cl)6 (para -chlorophenylalanine), Abu15 (α-aminobutyric acid),Nle27 ]hGH-RH(1–29)NH2 and contained Arg,d -Arg, homoarginine (Har), norleucine (Nle), and other substitutions. The following analogs were determined to have a high and/or protracted antagonistic activity: [PhAc-Tyr1 ,d -Arg2 ,Phe(4-Cl)6 ,Arg9 ,Abu15 ,Nle27 ,d -Arg29 ]hGH-RH(1–29)NH2 (JV-1–10), [PhAc-Tyr1 ,d -Arg2 ,Phe(4-Cl)6 ,Abu15 ,Nle27 ,d -Arg28 ,Har29 ]hGH-RH(1–29)NH2 (MZ-6–55), [PhAc-Tyr1 ,d -Arg2 ,Phe(4-Cl)6 ,Arg9 ,Abu15 ,Nle27 ,d -Arg28 ,Har29 ]hGH-RH(1–29)NH2 (JV-1–36), and [PhAc-Tyr1 ,d -Arg2 ,Phe(4-Cl)6 ,Har9 ,Tyr(Me)10 ,Abu15 ,Nle27 ,d -Arg28 ,Har29 ]hGH-RH(1–29)NH2 (JV-1–38). Among the peptides tested, analog JV-1–36 showed the highest GH-RH antagonistic activityin vitro and also induced a strong and prolonged inhibition of GH releasein vivo for at least 30 min. The antagonist JV-1–38 was slightly less potent than JV-1–36 bothin vitro andin vivo but proved to be very long-actingin vivo , suppressing the GH-RH-induced GH release even after 60 min. High and protractedin vivo activities of these antagonists indicate an improvement over earlier GH-RH analogs. Some of these hGH-RH antagonists could find clinical applications in the treatment of cancers dependent on insulin-like growth factors I and II.